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The Chemistry and Pharmacology of Synthetic Cannabinoid Receptor Agonist New Psychoactive Substances: Evolution

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New Psychoactive Substances

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 252))

Abstract

Synthetic cannabinoid receptor agonists (SCRAs) are the largest and most structurally diverse class of new psychoactive substances (NPS). Although the earliest SCRA NPS were simply repurposed from historical academic manuscripts or pharmaceutical patents describing cannabinoid ligands, recent examples bear hallmarks of rational design. SCRA NPS manufacturers have applied traditional medicinal chemistry strategies (such as molecular hybridization, bioisosteric replacement, and scaffold hopping) to existing cannabinoid templates in order to generate new molecules that circumvent structure-based legislation. Most SCRAs potently activate cannabinoid type 1 and type 2 receptors (CB1 and CB2, respectively), with the former contributing to the psychoactivity of these substances. SCRAs are generally more toxic than the Δ9-tetrahydrocannabinol (Δ9-THC) found in cannabis, and this may be due to ligand bias, metabolism, or off-target activity. This chapter will chart the evolution of recently identified SCRA NPS chemotypes, as well as their putative manufacturing by-products and thermolytic degradants, and describe structure-activity relationships within each class.

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Abbreviations

Δ9-THC:

(6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-dibenzo[b,d]pyran-1-ol (Δ9-tetrahydrocannabinol)

3-CAF:

Naphthalen-2-yl 1-(2-fluorophenyl)-1H-indazole-3-carboxylate

4-HTMPIPO:

4-Hydroxy-3,3,4-trimethyl-1-(1-pentyl-1H-indol-3-yl)pentan-1-one

5Cl-NNEI:

1-(5-Chloropentyl)-N-(naphthalen-1-yl)-1H-indole-3-carboxamide

5Cl-UR-144:

[1-(5-Chloropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone

5F-AB-FUPPYCA:

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-(5-fluoropentyl)-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide

5F-AB-PICA:

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-(5-fluoropentyl)-1H-indole-3-carboxamide

5F-AB-PINACA:

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-(5-fluoropentyl)-1H-indazole-3-carboxamide

5F-ADB-PICA:

N-[(2S)-1-Amino-3,3-dimethyl-1-oxobutan-2-yl]-1-(5-fluoropentyl)-1H-indole-3-carboxamide

5F-ADB-PINACA:

N-[(2S)-1-Amino-3,3-dimethyl-1-oxobutan-2-yl]-1-(5-fluoropentyl)-1H-indazole-3-carboxamide

5F-AKB-57:

Adamantan-1-yl 1-(5-fluoropentyl)-1H-indazole-3-carboxylate

5F-AKB-48-7N:

N-(Adamantan-1-yl)-1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

5F-AMB-PICA:

Methyl (2S)-2-{[1-(5-fluoropentyl)-1H-indole-3-carbonyl]amino}-3-methylbutanoate

5F-AMB-PINACA:

Methyl (2S)-2-{[1-(5-fluoropentyl)-1H-indazole-3-carbonyl]amino}-3-methylbutanoate

5F-AMPPPCA:

N-(Adamantan-1-yl)-1-(5-fluoropentyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamide

5F-APICA:

N-(Adamantan-1-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide

5F-APINACA:

N-(Adamantan-1-yl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide

5F-CUMYL-PICA:

1-(5-Fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide

5F-CUMYL-PINACA:

1-(5-Fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide

5F-MDMB-PICA:

Methyl (2S)-2-{[1-(5-fluoropentyl)-1H-indole-3-carbonyl]amino}-3,3-dimethylbutanoate

5F-MDMB-PINACA:

Methyl (2S)-2-{[1-(5-fluoropentyl)-1H-indazole-3-carbonyl]amino}-3,3-dimethylbutanoate

5F-MN-18:

1-(5-Fluoropentyl)-N-(naphthalen-1-yl)-1H-indazole-3-carboxamide

5F-NNEI:

1-(5-Fluoropentyl)-N-(naphthalen-1-yl)-1H-indole-3-carboxamide

5F-NPB-22-7N:

Quinolin-8-yl 1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate

5F-PB-22:

Quinolin-8-yl 1-(5-fluoropentyl)-1H-indole-3-carboxylate

5F-PCN:

1-(5-Fluoropentyl)-N-(naphthalen-1-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxamide

5F-SBD-005:

Naphthalen-1-yl 1-(5-fluoropentyl)-1H-indazole-3-carboxylate

A-836339:

N-(3-(2-methoxyethyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide

AB-001:

(Adamantan-1-yl)(1-pentyl-1H-indol-3-yl)methanone

AB-005-azepane:

(1-(1-Methylazepan-3-yl)-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone

AB-CHFUPYCA:

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-(cyclohexylmethyl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide

AB-CHMINACA:

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide

AB-CHMINACA-2H-indazole:

N-(1-Amino-3-methyl-1-oxobutan-2-yl)-2-(cyclohexylmethyl)-2H-indazole-3-carboxamide

AB-FUBICA:

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indole-3-carboxamide

AB-FUBINACA:

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide

AB-PICA:

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-pentyl-1H-indole-3-carboxamide

AB-PINACA:

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-pentyl-1H-indazole-3-carboxamide

ADB-CHMINACA:

N-[(2S)-1-Amino-3,3-dimethyl-1-oxobutan-2-yl]-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide

ADB-FUBICA:

N-[(2S)-1-Amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indole-3-carboxamide

ADB-FUBINACA:

N-[(2S)-1-Amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide

ADB-PICA:

N-[(2S)-1-Amino-3,3-dimethyl-1-oxobutan-2-yl]-1-pentyl-1H-indole-3-carboxamide

ADSB-FUB-187:

7-Chloro-N-[(2S)-1-({2-[(cyclopropanesulfonyl)amino]ethyl}amino)-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide

APP-FUBINACA:

N-[(2S)-1-Amino-1-oxo-3-phenylpropan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide

AKB-48:

N-(Adamantan-1-yl)-1-pentyl-1H-indazole-3-carboxamide

AM-2201:

[1-(5-Fluoropentyl)-1H-indol-3-yl](naphthalen-1-yl)methanone

AMB-CHMICA:

Methyl (2S)-2-{[1-(cyclohexylmethyl)-1H-indole-3-carbonyl]amino}-3-methylbutanoate

AMB-CHMINACA:

Methyl (2S)-2-{[1-(cyclohexylmethyl)-1H-indazole-3-carbonyl]amino}-3-methylbutanoate

AMB-FUBICA:

Methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H-indole-3-carbonyl}amino)-3-methylbutanoate

AMB-FUBINACA:

Methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}amino)-3-methylbutanoate

AMB-PICA:

Methyl (2S)-2-[(1-pentyl-1H-indole-3-carbonyl)amino]-3-methylbutanoate

AMB-PINACA:

Methyl (2S)-2-[(1-pentyl-1H-indazole-3-carbonyl)amino]-3-methylbutanoate

AMPPPCA:

N-(Adamantan-1-yl)-4-methyl-1-pentyl-5-phenyl-1H-pyrazole-3-carboxamide

APICA:

N-(Adamantan-1-yl)-1-pentyl-1H-indole-3-carboxamide

APINAC:

Adamantan-1-yl 1-pentyl-1H-indazole-3-carboxylate

APINACA:

N-(Adamantan-1-yl)-1-pentyl-1H-indazole-3-carboxamide

APINACA-2H-indazole:

N-(Adamantan-1-yl)-2-pentyl-2H-indazole-3-carboxamide

BB-22:

Quinolin-8-yl 1-(cyclohexylmethyl)-1H-indole-3-carboxylate

BIM-018:

(Naphthalen-1-yl)(1-pentyl-1H-benzimidazol-2-yl)methanone

BiPICANA:

N-(Naphthalen-1-yl)-1-pentyl-N-(1-pentyl-1H-indole-3-carbonyl)-1H-indole-3-carboxamide

BzODZ-EPyr:

3-Benzyl-5-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-3-yl)-1,2,4-oxadiazole

CBL-018:

Naphthalen-1-yl 1-pentyl-1H-indole-3-carboxylate

CBL-2201:

Naphthalen-1-yl 1-(5-fluoropentyl)-1H-indole-3-carboxylate

CP 47,497-C8:

2-[(1S,3R)-3-Hydroxycyclohexyl]-5-(2-methylnonan-2-yl)phenol

CUMYL-4CN-B7AICA:

1-(4-Cyanobutyl)-N-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

CUMYL-5F-P7AICA:

1-(5-Fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

CUMYL-BICA:

1-Butyl-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide

CUMYL-BINACA:

1-Butyl-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide

CUMYL-CHMICA:

1-(Cyclohexylmethyl)-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide

CUMYL-CHMINACA:

1-(Cyclohexylmethyl)-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide

CUMYL-FUBICA:

1-(4-Fluorobenzyl)-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide

CUMYL-FUBINACA:

1-(4-Fluorobenzyl)-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide

CUMYL-PEGACLONE:

5-Pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one

CUMYL-PICA:

1-Pentyl-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide

CUMYL-PINACA:

1-Pentyl-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide

DP-UR-144:

(1H-Indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone

EG-018:

(Naphthalen-1-yl)(9-pentyl-9H-carbazol-3-yl)methanone

EG-2201:

[9-(5-Fluoropentyl)-9H-carbazol-3-yl](naphthalen-1-yl)methanone

FAB-144:

[1-(5-Fluoropentyl)-1H-indazol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone

FDU-NNEI:

1-[(4-Fluorophenyl)methyl]-N-(naphthalen-1-yl)-1H-indole-3-carboxamide

FDU-PB-22:

Naphthalen-1-yl 1-[(4-fluorophenyl)methyl]-1H-indole-3-carboxylate

FUB-144:

{1-[(4-Fluorophenyl)methyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone

FUB-AKB-48:

N-(Adamantan-1-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide

FUB-PB-22:

Quinolin-8-yl 1-[(4-fluorophenyl)methyl]-1H-indole-3-carboxylate

FUBIMINA:

[1-(5-Fluoropentyl)-1H-benzimidazol-2-yl](naphthalen-1-yl)methanone

JWH-018:

(Naphthalen-1-yl)(1-pentyl-1H-indol-3-yl)methanone

M-5FPIC:

Methyl 1-(5-fluoropentyl)-1H-indole-3-carboxylate

MCBH-1:

1-(Cyclohexylmethyl)-2-(4-ethoxybenzyl)-N,N-diethyl-1H-benzo[d]imidazole-5-carboxamide

M-CHMIC:

Methyl 1-(cyclohexylmethyl)-1H-indole-3-carboxylate

MDMB-CHMCZCA:

Methyl (2S)-2-{[9-(cyclohexylmethyl)-9H-carbazole-3-carbonyl]amino}-3,3-dimethylbutanoate

MDMB-CHMICA:

Methyl (2S)-2-{[1-(cyclohexylmethyl)-1H-indole-3-carbonyl]amino}-3,3-dimethylbutanoate

MDMB-CHMINACA:

Methyl (2S)-2-{[1-(cyclohexylmethyl)-1H-indazole-3-carbonyl]amino}-3,3-dimethylbutanoate

MDMB-FUBICA:

Methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H-indole-3-carbonyl}amino)-3,3-dimethylbutanoate

MDMB-FUBINACA:

Methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}amino)-3,3-dimethylbutanoate

MDMB-PICA:

Methyl (2S)-3,3-dimethyl-2-[(1-pentyl-1H-indole-3-carbonyl)amino]butanoate

MDMB-PINACA:

Methyl (2S)-3,3-dimethyl-2-[(1-pentyl-1H-indazole-3-carbonyl)amino]butanoate

MEPIRAPIM:

(4-Methylpiperazin-1-yl)(1-pentyl-1H-indol-3-yl)methanone

MN-001:

(1-Pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone

MN-18:

N-(Naphthalen-1-yl)-1-pentyl-1H-indazole-3-carboxamide

MN-25:

7-Methoxy-1-[2-(morpholin-4-yl)ethyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-1H-indole-3-carboxamide

NMP-7:

(9-Pentyl-9H-carbazol-3-yl)(piperidin-1-yl)methanone

NNEI:

N-(Naphthalen-1-yl)-1-pentyl-1H-indazole-3-carboxamide

NNEI-2H-indazole:

N-(Naphthalen-1-yl)-2-pentyl-2H-indazole-3-carboxamide

NNL-3:

1-{[1-(5-Fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]oxy}-1H-benzotriazole

N-Phenyl-SDB-006:

1-Pentyl-N-phenyl-1H-indole-3-carboxamide

Org-28611:

(S)-(1-(Cyclohexylmethyl)-7-methoxy-1H-indol-3-yl)(3,4-dimethylpiperazin-1-yl)methanone

PB-22:

Quinolin-8-yl 1-pentyl-1H-indole-3-carboxylate

PTI-1:

N-Ethyl-N-{[2-(1-pentyl-1H-indol-3-yl)-1,3-thiazol-4-yl]methyl}ethanamine

PTI-2:

N-(2-Methoxyethyl)-N-{[2-(1-pentyl-1H-indol-3-yl)-1,3-thiazol-4-yl]methyl}propan-2-amine

QMPSB:

Quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate

RCS-4-N-Me:

(4-Methoxyphenyl)(1-methyl-1H-indol-3-yl)methanone

SBD-005:

Naphthalen-1-yl 1-pentyl-1H-indazole-3-carboxylate

SBD-006:

N-Benzyl-1-pentyl-1H-indole-3-carboxamide

THJ-018:

(Naphthalen-1-yl)(1-pentyl-1H-indazol-3-yl)methanone

THJ-2201:

[1-(5-Fluoropentyl)-1H-indazol-3-yl](naphthalen-1-yl)methanone

TMCP-020:

(1-Heptyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone

UR-144:

(1-Pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone

XLR-11:

[1-(5-Fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone

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Authors and Affiliations

  1. Department of Pathology, Stanford University, Stanford, CA, USA

    Samuel D. Banister

  2. Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia

    Samuel D. Banister

  3. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia

    Mark Connor

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  1. Samuel D. Banister
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Correspondence to Samuel D. Banister .

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  1. Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg (Saar), Germany

    Hans H. Maurer

  2. School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK

    Simon D. Brandt

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Banister, S.D., Connor, M. (2018). The Chemistry and Pharmacology of Synthetic Cannabinoid Receptor Agonist New Psychoactive Substances: Evolution. In: Maurer, H., Brandt, S. (eds) New Psychoactive Substances . Handbook of Experimental Pharmacology, vol 252. Springer, Cham. https://doi.org/10.1007/164_2018_144

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